Pyrrolo[2,3-d]pyrimidines have attracted much interest because of their biological importance. See, e.g., Choi, H. -S., et al., Bioorg. Med. Chem. Lett. 16:2689-2692 (2006); Choi, H. -S., et al., Bioorg. Med. Chem. Lett. 16:2173-2176 (2006); Smalley, T. L., et al., Bioorg. Med. Chem. Lett. 16:2091-2094 (2006); Gangjee, A., et al., J. Med. Chem. 49:1055-1065 (2006); Seela, F. and Peng, X., J. Org. Chem. 71:81-90 (2006); Foloppe, N., et al., J. Med. Chem. 48:4332-4345 (2005); Kempson, J., et al., Bioorg. Med. Chem. Lett. 15:1829-1833 (2005); Traxler, Peter, et al., Med. Res. Rev. 21:499-512 (2001). Syntheses of pyrrolo[2,3-d]pyrimidines typically require the preparation of 5-alkyl-7H-pyrrolo[2,3-d]pyrimidin-4-ol intermediates. See, e.g., U.S. patent application Ser. No. 11/354,636, filed Feb. 15, 2006. But despite their importance, few methods are known for preparing 5-alkyl-7H-pyrrolo[2,3-d]pyrimidin-4-ols with wide applicability. See e.g., Amarnath and Madhav, Synthesis, 837 (1974).
Typical synthetic methods include a desulfurization step, as illustrated in Scheme 1:
See, e.g., West, J. Org. Chem. 26:4959 (1961); Aono et al., EP 0733633-B1. Desulfurization is typically carried out using Raney Nickel in large excess, which can result in large amounts of heavy metal waste. In addition, when R is methyl, the process requires long heating times. See, e.g., U.S. patent application Ser. No. 11/354,636, filed Feb. 15, 2006. When R is hydrogen, the desulfurization is typically faster, but it requires multiple steps and provides lower yields.
5-Alkyl-7H-pyrrolo[2,3-d]pyrimidin-4-ols can also be prepared from the cyanopyrrole 3, as illustrated below in Scheme 2:
See e.g., Wamhoff and Wehling, Synthesis 51 (1976). Unfortunately, this reaction uses harsh conditions and provides poor yields. See also, Girgis et al., Synthesis 101 (1985). Consequently, new methods of preparing 5-alkyl-7H-pyrrolo[2,3-d]pyrimidin-4-ols are needed.